WO1996009290A1 - Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof - Google Patents
Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof Download PDFInfo
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- WO1996009290A1 WO1996009290A1 PCT/GB1995/002247 GB9502247W WO9609290A1 WO 1996009290 A1 WO1996009290 A1 WO 1996009290A1 GB 9502247 W GB9502247 W GB 9502247W WO 9609290 A1 WO9609290 A1 WO 9609290A1
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- enantiomer
- racemisation
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000009466 transformation Effects 0.000 title claims abstract description 8
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 229960004288 levobupivacaine Drugs 0.000 title claims description 4
- 239000002253 acid Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- -1 piperidine-2-carboxanilide compound Chemical class 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000006184 cosolvent Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 8
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 229960003150 bupivacaine Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 3
- MFCCQIZJSIYKQV-UHFFFAOYSA-N n-phenylpiperidine-2-carboxamide Chemical compound C1CCCNC1C(=O)NC1=CC=CC=C1 MFCCQIZJSIYKQV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 150000002391 heterocyclic compounds Chemical class 0.000 claims 1
- 125000006413 ring segment Chemical group 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 1
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 2-Desoxy-D-glycero-tetronsaeure Natural products OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 1
- BTXXTMOWISPQSJ-UHFFFAOYSA-N 4,4,4-trifluorobutan-2-one Chemical compound CC(=O)CC(F)(F)F BTXXTMOWISPQSJ-UHFFFAOYSA-N 0.000 description 1
- BQACOLQNOUYJCE-FYZZASKESA-N Abietic acid Natural products CC(C)C1=CC2=CC[C@]3(C)[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1 BQACOLQNOUYJCE-FYZZASKESA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960001549 ropivacaine Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
Definitions
- This invention relates to the racemisation and dynamic resolution of optically-enriched heterocyclic carboxanilides, e.g. piperidine-2-carboxanilides such as levobupivacaine.
- Background of the Invention Compounds of formula 1 (see formulae, below) wherein R is methyl, n-propyl, n-butyl or cyclopropyl and R is a 2,6-dimethylphenyl have utility as local anaesthetics. Biological studies have shown that (S)-enantiomers of such compounds display lower cardiotoxicity than the corresponding racemates whilst maintaining the same anaesthetic potency, and are therefore potentially more beneficial for clinical uses.
- N-heterocyclic-2-carboxanilides including compounds of formula l wherein R is H, methyl, n-propyl, n-butyl or cyclopropyl and R 2 is phenyl optionally substituted with one or more methyl groups, undergo rapid racemisation when heated in solution in the presence of a carboxylic acid R C0 2 H wherein R is either n-alkyl or aryl (exemplified in Scheme 1) or any acid having a pKa of -1 to +6, relative to water.
- the reaction can be carried out in a wholly or substantially non-aqueous system, e.g.
- a suitable cosolvent such as xylene allows the reaction to be conducted at optimum temperature, i.e. about 130°C.
- Any suitable chiral acid can be used; examples include L- and D-tartaric acid, and 0,0-dibenzoyl and 0,0-ditoluoyl derivatives thereof; (R)- and (S)-10-camphorsulphonic acid; (J?)- and (S)-mandelic acid; (R)- and (S)-malic acid; (R) - and (S) -1 ,l -binaphthyl-2,2 , -diyl hydrogen phosphate; and abietic acid.
- An important aspect of this invention relates to the ability to operate the process on an industrial scale.
- This in turn means that the optically-enriched carboxanilides themselves, e.g. obtained by resolution but to an extent that the predominant enantiomer is insufficiently enantiopure for immediate use, become useful products.
- a mixture enriched in (iR)-bupivacaine can be used practically, by racemisation of the mixture and subsequent resolution.
- the following Example illustrates the invention.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Peptides Or Proteins (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Measurement Of Radiation (AREA)
Abstract
A process for the racemisation of an optically-enriched piperidine-2-carboxanilide compound, comprises heating the compound in the presence of an alkanoic or arylalkanoic acid. A process for the asymmetric transformation of such a compound comprises heating the compound in the presence of an acid as defined above, a chiral acid resolving agent and an inert cosolvent.
Description
RACEMISATION AND ASYMMETRIC TRANSFORMATION PROCESSES USED IN THE MANUFACTURE OF LEVOBUPIVACAINE
AND ANALOGUES THEREOF Field of the Invention This invention relates to the racemisation and dynamic resolution of optically-enriched heterocyclic carboxanilides, e.g. piperidine-2-carboxanilides such as levobupivacaine. Background of the Invention Compounds of formula 1 (see formulae, below) wherein R is methyl, n-propyl, n-butyl or cyclopropyl and R is a 2,6-dimethylphenyl have utility as local anaesthetics. Biological studies have shown that (S)-enantiomers of such compounds display lower cardiotoxicity than the corresponding racemates whilst maintaining the same anaesthetic potency, and are therefore potentially more beneficial for clinical uses. Thus there is a requirement for efficient processes to manufacture compounds of formula 1 in the form of single enantiomers. For this purpose, conventional resolution approaches invariably afford up to 50% of the unwanted enantiomer. To improve atom utilisation in such processes, it is desirable to recycle the unwanted enantiomer by effecting its racemisation to provide material suitable for subsequent resolution. Additional benefits may be attainable by "asymmetric transformation", comprising simultaneous racemisation and crystallisation-induced resolution in a one-pot process.
Fyhr et al , Acta Pharm. Suecica 25(3) :121-132 (1988), disclose the racemisation of ropicavaine hydrochloride (1.HC1, R1 = Λ-propyl, R2 = 2,6-dimethylphenyl, absolute configuration = S) in dilute aqueous solution at pH 1-6, using HC1, and 80-130°C. The results are presented as a preformulation stability study and merely serve to indicate that ropivacaine racemises slowly in aqueous media. Shiraiwa et al , Bull. Chem. Soc. Jpn. 64:3251-3255 (1991) , disclose asymmetric transformation of 2-piperidine- carboxylic acid, by heating in an alkanoic acid solvent in
the presence of an chiral acid resolving agent and an aldehyde. The latter component is believed to assist racemisation by formation of a cationic Schiff base intermediate, a mechanistic pathway which can also operate on piperidine-2-carboxanilides 1 only in cases where R1 = H. Again, this process is unsuitable for operation on a manufacturing scale, not least because it uses environmentally-unacceptable reagents. Summary of the Invention The present invention is based on the suprising discovery that N-heterocyclic-2-carboxanilides, including compounds of formula l wherein R is H, methyl, n-propyl, n-butyl or cyclopropyl and R2 is phenyl optionally substituted with one or more methyl groups, undergo rapid racemisation when heated in solution in the presence of a carboxylic acid R C02H wherein R is either n-alkyl or aryl (exemplified in Scheme 1) or any acid having a pKa of -1 to +6, relative to water. The reaction can be carried out in a wholly or substantially non-aqueous system, e.g. either in a solution of neat acid or in the presence of an inert cosolvent such as xylene or toluene. The presence of residual salt forms of compounds of formula 1, e.g. as the result of resolution using a chiral resolving agent, do not impede the efficiency of the process. A preferred embodiment of the invention is the racemisation of bupivacaine (1, R = n-butyl, R2 = 2,6- dimethylphenyl) enriched in one enantiomer, preferably the (J?)-enantiomer, by heating with propanoic acid or butanoic acid. A suitable cosolvent such as xylene allows the reaction to be conducted at optimum temperature, i.e. about 130°C. Compared to the prior art, this process, and processes of the invention in general, afford significant advantages since neither dilute aqueous solutions ([l] <50 mM) nor extended reactions times are required. As a further feature of the invention, it has been discovered that asymmetric transformation of the N- heterocyclic-2-carboxanilides can be achieved by including
a chiral acid resolving agent as an additional component in the processes described above (exemplified in Scheme 2) . Two variants of such transformations are possible: firstly, a one-pot process in which a given enantiomer of the carboxanilide is converted to its optical antipode by heating to effect racemisation, followed by addition of a chiral acid, resulting in diastereoselective crystallisation of a salt; and secondly, the use of pre-formed racemic carboxanilide as a starting material. Any suitable chiral acid can be used; examples include L- and D-tartaric acid, and 0,0-dibenzoyl and 0,0-ditoluoyl derivatives thereof; (R)- and (S)-10-camphorsulphonic acid; (J?)- and (S)-mandelic acid; (R)- and (S)-malic acid; (R) - and (S) -1 ,l -binaphthyl-2,2,-diyl hydrogen phosphate; and abietic acid.
An important aspect of this invention relates to the ability to operate the process on an industrial scale. This in turn means that the optically-enriched carboxanilides themselves, e.g. obtained by resolution but to an extent that the predominant enantiomer is insufficiently enantiopure for immediate use, become useful products. This applies to mixtures of enantiomers in which one, usually the (R)-enantiomer, is present in an enantiomeric excess of 20 to 80%, preferably 25 to 75%, more preferably 30 to 70%, and most preferably 35 to 65%, with respect to its optical antipode. For example, a mixture enriched in (iR)-bupivacaine can be used practically, by racemisation of the mixture and subsequent resolution. The following Example illustrates the invention. Example
A stirred mixture of (S)-bupivacaine (0.140 g, 0.49 mmol) and propanoic acid (3.5 ml) was heated to reflux under a nitrogen atmosphere for 7 hours. The resulting solution was cooled and then poured into a mixture of distilled water (20 ml) and ethyl acetate (20 ml)'. Aqueous ammonia (28% w/v) was added until the pH of the aqueous
layer was 10. The organic layer was separated and the aqueous layer extracted with ethyl acetate (20 ml) . The combined organic extracts were washed with distilled water (20 ml) , dried (MgS04) and concentrated under reduced pressure to give racemic bupivacaine (0.137 g, 98%).
Scheme 1
(optically enriched) (racemic)
Scheme 2
(racemic) (optically enriched)
Claims
1. A process for the racemisation of an optically- enriched chiral N-containing heterocyclic compound having 3 to 7 ring atoms, and a 2-carboxanilide group, which comprises heating the compound in the presence of an acid selected from alkanoic acids, arylalkanoic acids and acids having a pKa of -1 to +6, relative to water.
2. A process according to claim 1, wherein the compound is a piperidine-2-carboxanilide.
3. A process according to claim 1, wherein the compound is of formula (1)
wherein R is H or a substituent of up to 20 C atoms and R is alkyl or aryl of up to 20 C atoms.
4. A process according to claim 3, wherein R is C6.20 aryl.
5. A process according to claim 4, wherein R is C 6 alkyl and R is phenyl optionally substituted with one or more C,_4 alkyl groups.
6. A process according to claim 5, wherein the starting material is optically-enriched bupivacaine, i.e. R is n- butyl and R is 2,6-dimethylphenyl.
7. A process according to claim 6, wherein the starting material is enriched in the (R)-enantiomer.
8. A process according to claim 5, wherein R is H, methyl, n-propyl or cyclopropyl and R is 2,6- dimethylphenyl.
9. A process according to any preceding claim, wherein the racemisation is carried out in a solution of the acid, neat or mixed with an inert cosolvent.
10. A process according to claim 9, wherein a solution of optically-enriched bupivacaine is heated in propanoic acid or butanoic acid.
11. A process for the asymmetric transformation of a compound as defined in any of claims 1 to 8, which comprises heating the compound in the presence of an acid as defined in claim 1, a chiral acid resolving agent and an inert cosolvent.
12. A process according to claim 11, wherein the compound, optically-enriched in a given enantiomer, is converted to its optical antipode.
13. A process according to claim 11, wherein racemic compound is transformed.
14. A process according to any preceding claim, wherein the acid is an alkanoic or arylalkanoic acid.
15. A process according to any of claims 1 to 13, wherein the acid has the given pKa.
16. A mixture of enantiomers of a compound as defined in any preceding claim, in which one enantiomer is in an excess of 20 to 80%, e.g. 30 to 70%, with respect to the other enantiomer.
17. A mixture according to claim 16, wherein said one enantiomer is the (R)-enantiomer.
18. Use of a mixture according to claim 16 or claim 17, for the manufacture of levobupivacaine, by racemisation of the mixture and subsequent resolution.
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL95319368A PL183204B1 (en) | 1994-09-23 | 1995-09-22 | Racemisation and dissymmetrical transformation processes used in obtaining levobupivacaine and its analoques |
| CA002200490A CA2200490C (en) | 1994-09-23 | 1995-09-22 | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof |
| DE69525950T DE69525950T2 (en) | 1994-09-23 | 1995-09-22 | RACEMIZATION PROCESS IN THE PRODUCTION OF LEVOBUPIVACAINE AND ANALOGS |
| DK95932092T DK0782569T3 (en) | 1994-09-23 | 1995-09-22 | Racemization procedure used in the preparation of levobupivacaine and analogs thereof |
| AT95932092T ATE214695T1 (en) | 1994-09-23 | 1995-09-22 | RACEMIZATION PROCESS IN THE PRODUCTION OF LEVOBUPIVACAINE AND ANALOGUES |
| JP51069496A JP3898220B2 (en) | 1994-09-23 | 1995-09-22 | Racemization and asymmetric transformation methods used in the production of levobupivacaine and its analogues |
| AU35279/95A AU695479B2 (en) | 1994-09-23 | 1995-09-22 | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof |
| EP95932092A EP0782569B1 (en) | 1994-09-23 | 1995-09-22 | Racemisation process used in the manufacture of levobupivacaine and analogues thereof |
| MX9702210A MX9702210A (en) | 1994-09-23 | 1995-09-22 | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof. |
| US08/809,941 US5786484A (en) | 1994-09-23 | 1995-09-22 | Racemization and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof |
| FI971202A FI117436B (en) | 1994-09-23 | 1997-03-21 | Method for racemizing an optically enriched form of levobupivacaine and analogs thereof |
| NO971358A NO308074B1 (en) | 1994-09-23 | 1997-03-21 | Method for racemization of optically enriched heterocyclic carboxanilides |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP94306962.5 | 1994-09-23 | ||
| EP94306962 | 1994-09-23 | ||
| GBGB9504927.6A GB9504927D0 (en) | 1995-03-10 | 1995-03-10 | Racemisation and asymmetric transformation |
| GB9504927.6 | 1995-03-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996009290A1 true WO1996009290A1 (en) | 1996-03-28 |
Family
ID=26137306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1995/002247 WO1996009290A1 (en) | 1994-09-23 | 1995-09-22 | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5786484A (en) |
| EP (1) | EP0782569B1 (en) |
| JP (1) | JP3898220B2 (en) |
| KR (1) | KR100393133B1 (en) |
| CN (1) | CN1104416C (en) |
| AT (1) | ATE214695T1 (en) |
| AU (1) | AU695479B2 (en) |
| CA (1) | CA2200490C (en) |
| DE (1) | DE69525950T2 (en) |
| DK (1) | DK0782569T3 (en) |
| ES (1) | ES2173194T3 (en) |
| FI (1) | FI117436B (en) |
| HU (1) | HU216291B (en) |
| MX (1) | MX9702210A (en) |
| NO (1) | NO308074B1 (en) |
| PL (1) | PL183204B1 (en) |
| PT (1) | PT782569E (en) |
| WO (1) | WO1996009290A1 (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1067133A1 (en) * | 1999-07-09 | 2001-01-10 | F. Hoffmann-La Roche Ag | Process for the racemization of atropisomeric bis (phosphine oxide) compounds |
| WO2001076599A1 (en) * | 2000-04-06 | 2001-10-18 | Cristália Produtos Químicos Farmacéuticos Ltda. | Process of making racemic bupivacaine's enantiomers, levobupivacaine's pharmaceutical compositions, levobupivacaine's pharmaceutical compositions formulated on its free base form or its pharmaceutical acceptable salts and use of levobupivacaine's pharmaceutical compositions formulated on its free base form |
| WO2001096306A1 (en) * | 2000-06-16 | 2001-12-20 | Boehringer Ingelheim Pharma Kg | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
| US6384227B2 (en) | 1995-01-18 | 2002-05-07 | Darwin Discovery Ltd. | Racemisation process for use in the manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents |
| US6495694B2 (en) | 2000-06-16 | 2002-12-17 | Boehringer Ingelheim Pharma Kg | Efficient separation of enantiomers of piperidone derivatives by precipitation of the desired eantiomer during in situ racemization of the unwanted enantiomer |
| EP1295873A4 (en) * | 2000-06-14 | 2004-05-19 | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative | |
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| US8956644B2 (en) | 2006-11-03 | 2015-02-17 | Durect Corporation | Transdermal delivery systems |
| US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| US9592204B2 (en) | 2007-12-06 | 2017-03-14 | Durect Corporation | Oral pharmaceutical dosage forms |
| US9616055B2 (en) | 2008-11-03 | 2017-04-11 | Durect Corporation | Oral pharmaceutical dosage forms |
| US10471002B2 (en) | 2002-06-25 | 2019-11-12 | Durect Corporation | Short duration depot formulations |
| WO2019222565A1 (en) * | 2018-05-18 | 2019-11-21 | Kura Oncology, Inc. | Synthesis of tipifarnib |
| US11083796B2 (en) | 2005-07-26 | 2021-08-10 | Durect Corporation | Peroxide removal from drug delivery vehicle |
| US11400019B2 (en) | 2020-01-13 | 2022-08-02 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
| US12274794B2 (en) | 2016-07-06 | 2025-04-15 | Orient Pharma Co., Ltd. | Oral dosage form with drug composition, barrier layer and drug layer |
| US12433877B2 (en) | 2022-05-13 | 2025-10-07 | Durect Corporation | Sustained release drug delivery systems and related methods |
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| JP2000256359A (en) * | 1999-03-11 | 2000-09-19 | Japan Science & Technology Corp | Highly Selective Asymmetric Conversion of Molecular Groups with Planar Chirality |
| BRPI0104491B8 (en) * | 2001-10-10 | 2021-05-25 | Cristalia Produtos Quim Farmaceuticos Ltda | n-(2,6-dimethylphenyl)-1-propyl-2-piperidinecarboxamide; process of obtaining the enantiomers; non-racemic mixture of anantiomers and its process of obtaining and pharmaceutical composition. |
| CN102093284B (en) * | 2010-12-29 | 2013-05-08 | 宜昌人福药业有限责任公司 | Method for enriching piperidine-2-formanilide optically active compound |
| CN103664744B (en) * | 2013-11-30 | 2015-07-15 | 山东永泰化工有限公司 | Preparation method for levobupivacaine |
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1995
- 1995-09-22 AU AU35279/95A patent/AU695479B2/en not_active Expired
- 1995-09-22 HU HU9702212A patent/HU216291B/en unknown
- 1995-09-22 US US08/809,941 patent/US5786484A/en not_active Expired - Lifetime
- 1995-09-22 JP JP51069496A patent/JP3898220B2/en not_active Expired - Lifetime
- 1995-09-22 CN CN95195252A patent/CN1104416C/en not_active Expired - Lifetime
- 1995-09-22 KR KR1019970701774A patent/KR100393133B1/en not_active Expired - Lifetime
- 1995-09-22 DE DE69525950T patent/DE69525950T2/en not_active Expired - Lifetime
- 1995-09-22 PL PL95319368A patent/PL183204B1/en unknown
- 1995-09-22 EP EP95932092A patent/EP0782569B1/en not_active Expired - Lifetime
- 1995-09-22 WO PCT/GB1995/002247 patent/WO1996009290A1/en active IP Right Grant
- 1995-09-22 CA CA002200490A patent/CA2200490C/en not_active Expired - Lifetime
- 1995-09-22 AT AT95932092T patent/ATE214695T1/en active
- 1995-09-22 ES ES95932092T patent/ES2173194T3/en not_active Expired - Lifetime
- 1995-09-22 DK DK95932092T patent/DK0782569T3/en active
- 1995-09-22 MX MX9702210A patent/MX9702210A/en unknown
- 1995-09-22 PT PT95932092T patent/PT782569E/en unknown
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1997
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Cited By (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6384227B2 (en) | 1995-01-18 | 2002-05-07 | Darwin Discovery Ltd. | Racemisation process for use in the manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents |
| EP1067133A1 (en) * | 1999-07-09 | 2001-01-10 | F. Hoffmann-La Roche Ag | Process for the racemization of atropisomeric bis (phosphine oxide) compounds |
| WO2001076599A1 (en) * | 2000-04-06 | 2001-10-18 | Cristália Produtos Químicos Farmacéuticos Ltda. | Process of making racemic bupivacaine's enantiomers, levobupivacaine's pharmaceutical compositions, levobupivacaine's pharmaceutical compositions formulated on its free base form or its pharmaceutical acceptable salts and use of levobupivacaine's pharmaceutical compositions formulated on its free base form |
| US7700629B2 (en) | 2000-04-06 | 2010-04-20 | Cristalia Productos Quimicos Farmaceuticos Ltda | Use of a non-racemic mixture of bupivacaine enantiomers, for improving the anesthesia profile |
| EP1295873A4 (en) * | 2000-06-14 | 2004-05-19 | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative | |
| US6962998B2 (en) | 2000-06-14 | 2005-11-08 | Toray Industries, Inc. | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative |
| WO2001096306A1 (en) * | 2000-06-16 | 2001-12-20 | Boehringer Ingelheim Pharma Kg | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
| US6495694B2 (en) | 2000-06-16 | 2002-12-17 | Boehringer Ingelheim Pharma Kg | Efficient separation of enantiomers of piperidone derivatives by precipitation of the desired eantiomer during in situ racemization of the unwanted enantiomer |
| US10471002B2 (en) | 2002-06-25 | 2019-11-12 | Durect Corporation | Short duration depot formulations |
| US11179326B2 (en) | 2002-06-25 | 2021-11-23 | Durect Corporation | Short duration depot formulations |
| US10471001B2 (en) | 2002-06-25 | 2019-11-12 | Durect Corporation | Short duration depot formulations |
| US8945614B2 (en) | 2002-12-13 | 2015-02-03 | Durect Corporation | Oral drug delivery system |
| US9918982B2 (en) | 2002-12-13 | 2018-03-20 | Durect Corporation | Oral drug delivery system |
| US9517271B2 (en) | 2002-12-13 | 2016-12-13 | Durect Corporation | Oral drug delivery system |
| US8974821B2 (en) | 2002-12-13 | 2015-03-10 | Durect Corporation | Oral drug delivery system |
| US9233160B2 (en) | 2002-12-13 | 2016-01-12 | Durect Corporation | Oral drug delivery system |
| US8846072B2 (en) | 2004-09-17 | 2014-09-30 | Durect Corporation | Controlled delivery system |
| US11083796B2 (en) | 2005-07-26 | 2021-08-10 | Durect Corporation | Peroxide removal from drug delivery vehicle |
| US8956644B2 (en) | 2006-11-03 | 2015-02-17 | Durect Corporation | Transdermal delivery systems |
| US9655861B2 (en) | 2007-12-06 | 2017-05-23 | Durect Corporation | Oral pharmaceutical dosage forms |
| US10206883B2 (en) | 2007-12-06 | 2019-02-19 | Durect Corporation | Oral pharamaceutical dosage forms |
| US9592204B2 (en) | 2007-12-06 | 2017-03-14 | Durect Corporation | Oral pharmaceutical dosage forms |
| US10328068B2 (en) | 2008-11-03 | 2019-06-25 | Durect Corporation | Oral pharmaceutical dosage forms |
| US9616055B2 (en) | 2008-11-03 | 2017-04-11 | Durect Corporation | Oral pharmaceutical dosage forms |
| US9884056B2 (en) | 2008-11-03 | 2018-02-06 | Durect Corporation | Oral pharmaceutical dosage forms |
| US9907851B2 (en) | 2013-03-15 | 2018-03-06 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| US9855333B2 (en) | 2013-03-15 | 2018-01-02 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| US10300142B2 (en) | 2013-03-15 | 2019-05-28 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| US9572885B2 (en) | 2013-03-15 | 2017-02-21 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| US12274794B2 (en) | 2016-07-06 | 2025-04-15 | Orient Pharma Co., Ltd. | Oral dosage form with drug composition, barrier layer and drug layer |
| WO2019222565A1 (en) * | 2018-05-18 | 2019-11-21 | Kura Oncology, Inc. | Synthesis of tipifarnib |
| US11542244B2 (en) | 2018-05-18 | 2023-01-03 | Kura Oncology, Inc. | Synthesis of tipifarnib |
| US11771624B2 (en) | 2020-01-13 | 2023-10-03 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
| US11400019B2 (en) | 2020-01-13 | 2022-08-02 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
| US12433877B2 (en) | 2022-05-13 | 2025-10-07 | Durect Corporation | Sustained release drug delivery systems and related methods |
Also Published As
| Publication number | Publication date |
|---|---|
| NO971358D0 (en) | 1997-03-21 |
| AU695479B2 (en) | 1998-08-13 |
| CN1104416C (en) | 2003-04-02 |
| DE69525950D1 (en) | 2002-04-25 |
| HU216291B (en) | 1999-06-28 |
| JP3898220B2 (en) | 2007-03-28 |
| PL183204B1 (en) | 2002-06-28 |
| FI117436B (en) | 2006-10-13 |
| EP0782569B1 (en) | 2002-03-20 |
| ATE214695T1 (en) | 2002-04-15 |
| FI971202L (en) | 1997-03-21 |
| PL319368A1 (en) | 1997-08-04 |
| FI971202A0 (en) | 1997-03-21 |
| KR100393133B1 (en) | 2003-11-17 |
| DK0782569T3 (en) | 2002-07-22 |
| EP0782569A1 (en) | 1997-07-09 |
| MX9702210A (en) | 1998-05-31 |
| US5786484A (en) | 1998-07-28 |
| PT782569E (en) | 2002-09-30 |
| JPH10505855A (en) | 1998-06-09 |
| CA2200490A1 (en) | 1996-03-28 |
| NO971358L (en) | 1997-03-21 |
| HUT77055A (en) | 1998-03-02 |
| CN1159184A (en) | 1997-09-10 |
| NO308074B1 (en) | 2000-07-17 |
| ES2173194T3 (en) | 2002-10-16 |
| AU3527995A (en) | 1996-04-09 |
| CA2200490C (en) | 2007-01-09 |
| DE69525950T2 (en) | 2002-09-19 |
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